The modifier-of-deaf waddler (mdfw) is a hearing susceptibility locus which confers progressive hearing loss to CBy-dfw2J/+ heterozygous. Neither homozygosity at the mdfw locus nor heterozygosity at the dfw2J locus alone are sufficient to cause the observed hearing impairment indicating a synergistic interaction between the two loci. We identified the dfw gene and showed that mutations in the plasma membrane Ca2+ ATPase 2 gene (Atp2b2) are the cause of hearing loss and imbalance in two mutant strains of deaf waddler. We are now focusing on identifying the second component (mdfw) of this genetic interaction. We expanded the mapping cross and constructed an integrated genetic, radiation hybrid and BAC based physical map of markers around mdfw. We also fine-mapped the waltzer (v) mouse mutation and showed that v and mdfw localize to the same genetic interval. In the waltzer locus, we identified a novel cadherin gene, called Cadherin-23 (Cdh23). We identified mutations in Cdh23 in alleles of waltzer that cause the deafness/waltzing syndrome. We showed that the phenotype is due to a severe stereocilia disorganization in auditory and vestibular hair cells. Our discovery also led to the identification of human CDH23; mutations in the human homologue were shown to cause the deaf/blind disease Usher Syndrome type 1D. To evaluate Cdh23 as candidate gene for mdfw, we determined the nucleotide sequence of Cdh23 in several inbred strains, including CAST/Ei, V/Le, CBA/CaJ and BUB/BnJ. Between the BALB/c and CAST/Ei-derived sequence we found eleven amino acid substitutions; however none of these changes correlated with the segregation of mdfw.